PROJECT D: ELECTROPHYSIOLOGICAL STUDIES IN CANINE NARCOLEPSY The proposed research intends to establish a neurophysiological understanding of anatomical structure and neurotransmitter mechanisms involved in the control of sleepiness and cataplexy in narcolepsy. Previous work in our laboratory has established that the midbrain dopaminergic and pontine and basal forebrain (BF) cholinergic systems are critically involved in the control of sleepiness and cataplexy in narcolepsy. In this proposal, we will: (1) study how dopaminergic (DA) neurons in the ventral tegmental area (VTA) and substantia nigra (SN) regulate cataplexy and sleepiness. Our working hypothesis is that DA neurons are less active during cataplexy and are hypersensitive to autoinhibition by 2(3) stimulation in narcoleptic animals. (2) test the possibility that DA output neurons in the mesostriatal and mesolimbic systems are involved in the control of sleepiness in narcolepsy. DA uptake inhibitors significantly enhance alertness, but have no effect on cataplexy. In contrast, DA D2(3) agonists enhance both cataplexy and sleepiness. Since DA mesostriatal dopaminergic projects are important for the control of alertness, but not for cataplexy, and that these DA output neurons are hypersensitive to D2(3) stimulation in narcolepsy. (3) test the hypothesis that cholinergic inputs in the BF are critical for triggering cataplexy. We have found that stimulation of a cholinoceptive site in the BF induces cataplexy in narcoleptic canines, while it indices wake in control animals. We therefore hypothesize that some neurons in the BF are activated during cataplexy and by cholinergic stimulation. Extracellular single unit activity is measured in cataplexy (for narcoleptic canines) and other behavioral/sleep states (wake, drowsy, light sleep [LS], deep sleep [DS] and rapid eye movement [REM] sleep) in narcoleptic and control Dobermans under freely-moving conditions. Changes in the firing pattern of neurons across different sleep/behavioral states and in response to drug administration (dopaminergic and cholinergic compounds) will be analyzed. The results obtained from these experiments will allow us to better understand the fundamental mechanisms of neurophysiological control of sleepiness and cataplexy and their involvement in the pathophysiology of narcolepsy.